The overall goal of this research proposal (now being submitted competitively for its 3 cycle of funding) is to increase understanding of structural and functional changes as epilepsy evolves in order to improve the localization of epileptic foci for surgical treatment of medically-refractory epilepsy. Towards this goal, we have pioneered the use of 2-deoxy-2[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) positron emission tomography (PET) for better localization of the epileptic focus in children with epilepsy. Despite improvements in seizure focus localization using various technologies and improved surgical outcome, however, patients with extratemporal lobe epilepsy still do not achieve a 90% seizure-free outcome as is possible with temporal lobe epilepsy surgery. Surgical failures may be partly accounted for by two major findings from the previous funding period: (1) the site of seizure onset depicted by intracranial EEC is often not coincident with the site of significantly decreased FMZ binding, but is typically adjacent to it, and (2) there are often additional sites of decreased FMZ binding in cortex remote from, but in areas that are synaptically connected to, the primary seizure focus. We believe that we are beginning to identify, for the first time using a neuroimaging modality, the presence of secondary epileptic foci, which are known to exist and to account for surgical failures but have been difficult to identify preoperatively. The present proposal seeks to understand in great detail the formation, localization and connectivity of secondary epileptic foci by combining longitudinal measures of FMZ binding and diffusion tensor imaging in a cohort of children with newly-diagnosed partial epilepsy. In addition, we will undertake a cross-sectional study, which will relate FMZ binding and diffusion tensor imaging abnormalities of primary and secondary epileptic foci to intracranial electrophysiological measures in a subset of children undergoing epilepsy surgery. The aims being proposed in this application are a logical extension of the research and accomplishments of the previous funding period, and will contribute to further definition and clarification of primary and secondary epileptogenic brain regions during epilepsy surgery evaluation, with a goal towards better surgical outcome in children whose surgical success remains suboptimal at present.